bims-polyam 2019-12-08 papers

on Polyamines

Issue of 2019–12–08
ten papers selected by
Sebastian J. Hofer, University of Graz and Alexander Ivanov, Engelhardt Institute of Molecular Biology

Polyamine acetylation and substrate-induced oligomeric states in histone acetyltransferase of multiple drug resistant Acinetobacter baumannii.
Hypusine biosynthesis in β cells links polyamine metabolism to facultative cellular proliferation to maintain glucose homeostasis.
The curious case of polyamines: spermidine drives reversal of B cell senescence.
Ornithine decarboxylase inhibition downregulates multiple pathways involved in the formation of precancerous lesions of esophageal squamous cell cancer.
The polyamine transporter Slc18b1(VPAT) is important for both short and long time memory and for regulation of polyamine content in the brain.
The possible bottleneck effect of polyamines' catabolic enzymes in efficient adventitious rooting of two stone fruit rootstocks.
Plasma spermine levels in patients with schizophrenia and bipolar disorder: A preliminary study.
The effect of spermidine on guanine decomposition via photoinduced electron transfer in DNA.
Targeting metabolic dependencies in pediatric cancer.
Metabolic and transcriptional changes in seminal plasma of asthenozoospermia patients.

Biochimie. 2019 Nov 29. pii: S0300-9084(19)30338-4. [Epub ahead of print]168 268-276

Polyamine acetylation and substrate-induced oligomeric states in histone acetyltransferase of multiple drug resistant Acinetobacter baumannii.

Jyoti Singh Tomar, Ramakrishna Vijayacharya Hosur.

  Histone acetyltransferase (Hpa2) is an unusual acetyltransferase, with a wide range of substrates; including histones, polyamines and aminoglycosides antibiotic. Hpa2 belongs to GNAT superfamily and GNATs are well known for the formation of homo-oligomers. However, the reason behind their oligomerization remained unexplored. Here, oligomeric states of Hpa2 were explored, to understand the functional significance of oligomerization. Biochemical analysis suggests that Hpa2 exists as dimer in solution and self-assembles into tetramer in the spermine, spermidine and kanamycin bound form. Stability analysis with denaturants concludes that homo-oligomerization of Hpa2 relies on bound substrate and not on experimental conditions. Homo-oligomerization in Hpa2 depicts direct correlation with its polyamine acetylating capacity. This correlation and in silico model structures suggest that oligomerization of Hpa2 is associated with the hastening of acetylation process. Interestingly, polyamine acetylation down regulates biofilms formation in E. coli BL21/Hpa2-transformants cells. Therefore, we propose that Hpa2 manipulates survival strategies of the bacterium via polyamines and antibiotics acetylation.

Keywords:  Acetylation; Biofilms; Cross-linking; Homo-oligomer; Polyamine

DOI:  https://doi.org/10.1016/j.biochi.2019.11.015
Sci Signal. 2019 Dec 03. pii: eaax0715. [Epub ahead of print]12(610):

Hypusine biosynthesis in β cells links polyamine metabolism to facultative cellular proliferation to maintain glucose homeostasis.

Esther M Levasseur, Kentaro Yamada, Annie R Piñeros, Wenting Wu, Farooq Syed, Kara S Orr, Emily Anderson-Baucum, Teresa L Mastracci, Bernhard Maier, Amber L Mosley, Yunlong Liu, Ernesto Bernal-Mizrachi, Laura C Alonso, Donald Scott, Adolfo Garcia-Ocaña, Sarah A Tersey, Raghavendra G Mirmira.

Deoxyhypusine synthase (DHPS) uses the polyamine spermidine to catalyze the hypusine modification of the mRNA translation factor eIF5A and promotes oncogenesis through poorly defined mechanisms. Because germline deletion of Dhps is embryonically lethal, its role in normal postnatal cellular function in vivo remains unknown. We generated a mouse model that enabled the inducible, postnatal deletion of Dhps specifically in postnatal islet β cells, which function to maintain glucose homeostasis. Removal of Dhps did not have an effect under normal physiologic conditions. However, upon development of insulin resistance, which induces β cell proliferation, Dhps deletion caused alterations in proteins required for mRNA translation and protein secretion, reduced production of the cell cycle molecule cyclin D2, impaired β cell proliferation, and induced overt diabetes. We found that hypusine biosynthesis was downstream of protein kinase C-ζ and was required for c-Myc-induced proliferation. Our studies reveal a requirement for DHPS in β cells to link polyamines to mRNA translation to effect facultative cellular proliferation and glucose homeostasis.

DOI: https://doi.org/10.1126/scisignal.aax0715
Autophagy. 2019 Dec 03. 1-2

The curious case of polyamines: spermidine drives reversal of B cell senescence.

Shree Padma Metur, Daniel J Klionsky.

  Spermidine, a polyamine that induces macroautophagy/autophagy, exhibits anti-aging properties. It is thought that these properties of spermidine are primarily due to its ability to modulate autophagy, but the mechanistic details were hitherto unclear. Studying the effects of spermidine on B lymphocytes, Zhang et al uncover the molecular mechanism that places spermidine at the crossroads of autophagy and immune senescence. Their work highlights the role of spermidine as an anti-aging metabolite that exerts its effects through the translational control of autophagy.Abbreviations: EIF5A, eukaryotic translation initiation factor 5A; HC, hematopoietic cell; ODC1, ornithine decarboxylase 1; PBMCs, peripheral blood mononuclear cells.

Keywords:  Aging; EIF5A; hypusination; lysosome; macroautophagy; spermidine; stress; translation

DOI:  https://doi.org/10.1080/15548627.2019.1698210
Mol Carcinog. 2019 Dec 03.

Ornithine decarboxylase inhibition downregulates multiple pathways involved in the formation of precancerous lesions of esophageal squamous cell cancer.

Yifei Xie, Christopher D Dong, Qiong Wu, Yanan Jiang, Ke Yao, Jing Zhang, Simin Zhao, Ying Ren, Qiang Yuan, Xinhuan Chen, Zhongyi Liu, Jimin Zhao, Kangdong Liu.

  The high incidence and mortality of esophageal squamous cell cancer (ESCC) is a major health problem worldwide. Precancerous lesions of ESCC may either progress to cancer or revert to normal epithelium with appropriate interventions; the bidirectional instability of the precancerous lesions of ESCC provides opportunities for intervention. Reports suggest that the upregulation of ornithine decarboxylase (ODC) is closely related to carcinogenesis. In this study, we investigated whether ODC may act as a target for chemoprevention in ESCC. Immunohistochemistry (IHC) assays indicate that ODC expression is higher in esophageal precancerous lesions compared with normal tissue controls. Its overexpression promotes cell proliferation and transformation of normal esophageal epithelial cells, and its activity is increased after N-nitrosomethylbenzylamine (NMBA) induction in Shantou human embryonic esophageal cell line (SHEE) and human immortalized cells (Het1A) cells. In addition, p38 α, extracellular regulated kinase (ERK1/2) in the mitogen-activated protein kinase pathway and protein kinase B (AKT)/mammalian target of rapamycin (mTOR)/ribosomal protein S6 kinase (p70S6K) pathways are activated in response to NMBA treatment. Difluoromethylornithine (DFMO) is an ODC inhibitor, which inhibits NMBA-induced activation of p38 α, ERK1/2 and AKT/mTOR/p70S6K pathways; this has been verified by Western blotting. DFMO was also found to suppress the development of esophageal precancerous lesions in an NMBA-induced rat model; IHC demonstrated p38 α, ERK1/2, and AKT/mTOR/p70S6K pathways to be downregulated in these rats. These findings indicate the mechanisms by which ODC inhibition suppresses the development of esophageal precancerous lesions by downregulating p38 α, ERK1/2, and AKT/mTOR/p70S6k signaling pathways, ODC may be a potential target for chemoprevention in ESCC.

Keywords:  N-nitrosomethylbenzylamine; chemoprevention; esophageal neoplasms; ornithine decarboxylase inhibitor; preneoplastic

DOI:  https://doi.org/10.1002/mc.23144
PLoS Genet. 2019 Dec 04. 15(12): e1008455

The polyamine transporter Slc18b1(VPAT) is important for both short and long time memory and for regulation of polyamine content in the brain.

Robert Fredriksson, Smitha Sreedharan, Karin Nordenankar, Johan Alsiö, Frida A Lindberg, Ashley Hutchinson, Anders Eriksson, Sahar Roshanbin, Diana M Ciuculete, Anica Klockars, Aniruddha Todkar, Maria G Hägglund, Sofie V Hellsten, Viktoria Hindlycke, Åke Västermark, Ganna Shevchenko, Gaia Olivo, Cheng K, Klas Kullander, Ali Moazzami, Jonas Bergquist, Pawel K Olszewski, Helgi B Schiöth.

SLC18B1 is a sister gene to the vesicular monoamine and acetylcholine transporters, and the only known polyamine transporter, with unknown physiological role. We reveal that Slc18b1 knock out mice has significantly reduced polyamine content in the brain providing the first evidence that Slc18b1 is functionally required for regulating polyamine levels. We found that this mouse has impaired short and long term memory in novel object recognition, radial arm maze and self-administration paradigms. We also show that Slc18b1 KO mice have altered expression of genes involved in Long Term Potentiation, plasticity, calcium signalling and synaptic functions and that expression of components of GABA and glutamate signalling are changed. We further observe a partial resistance to diazepam, manifested as significantly lowered reduction in locomotion after diazepam treatment. We suggest that removal of Slc18b1 leads to reduction of polyamine contents in neurons, resulting in reduced GABA signalling due to long-term reduction in glutamatergic signalling.

DOI: https://doi.org/10.1371/journal.pgen.1008455
J Plant Physiol. 2019 Jun 13. pii: S0176-1617(19)30097-5. [Epub ahead of print]244 152999

The possible bottleneck effect of polyamines' catabolic enzymes in efficient adventitious rooting of two stone fruit rootstocks.

Athanasios Tsafouros, Peter A Roussos.

  Adventitious rooting is an important plant physiological response utilized in cutting propagation, a procedure with high financial significance. Many endogenous factors are involved, such as plant growth regulators, carbohydrates, minerals, polyamines etc. The objective of the present study was to investigate the role of polyamines and polyamine catabolic enzymes in the bases of softwood cuttings of two Prunus rootstocks, during the early phases of rhizogenesis. An easy-to-root and a difficult-to-root rootstock were studied, concerning their polyamine content (in free, soluble conjugate and insoluble bound form), polyamine catabolic enzyme activities (polyamine oxidase, PAO and diamine oxidase, DAO) and catalase activity, with and without the effect of indole-3-butyric acid as rooting hormone, during the early phases of rhizogenesis. Putrescine, spermine and their catabolic product, H2O2, were applied to test their function to rescue the rooting percentage of the recalcitrant species. Spermine was not detected in the difficult to root rootstock, which exhibited higher titer of putrescine and spermidine, PAO and catalase activity, but lower DAO activity compared to the easy-to-root one. The rooting percentage of the recalcitrant species was doubled under spermine and H2O2 application. The results obtained, highlighted the role of polyamine catabolic enzymes and indirectly the role of the polyamine catabolic product H2O2 as more significant than the polyamine content per se in adventitious rooting of the specific stone fruit rootstocks.

Keywords:  Catalase; Cuttings; DAO; Hydrogen peroxide; PAO; Prunus

DOI:  https://doi.org/10.1016/j.jplph.2019.152999
Schizophr Res. 2019 Dec 02. pii: S0920-9964(19)30547-X. [Epub ahead of print]

Plasma spermine levels in patients with schizophrenia and bipolar disorder: A preliminary study.

Muharrem Burak Baytunca, Dost Öngür.

DOI: https://doi.org/10.1016/j.schres.2019.11.040
Org Biomol Chem. 2019 Dec 04.

The effect of spermidine on guanine decomposition via photoinduced electron transfer in DNA.

Mayu Esumi, Shunsuke Sakurai, Makiko Tanaka.

Spermidine, a trivalent organic cation, induced DNA structural changes and suppressed guanine photooxidative decomposition via electron transfer through pyrene-modified DNA. On the other hand, adding higher concentrations of spermidine resulted in DNA condensation. The efficiency of guanine decomposition in condensed pyrene-modified DNA was promoted remarkably.

DOI: https://doi.org/10.1039/c9ob01860c
Curr Opin Pediatr. 2019 Nov 27.

Targeting metabolic dependencies in pediatric cancer.

Sameer H Issaq, Christine M Heske.

PURPOSE OF REVIEW: In an attempt to identify potential new therapeutic targets, efforts to describe the metabolic features unique to cancer cells are increasingly being reported. Although current standard of care regimens for several pediatric malignancies incorporate agents that target tumor metabolism, these drugs have been part of the therapeutic landscape for decades. More recent research has focused on the identification and targeting of new metabolic vulnerabilities in pediatric cancers. The purpose of this review is to describe the most recent translational findings in the metabolic targeting of pediatric malignancies.
RECENT FINDINGS: Across multiple pediatric cancer types, dependencies on a number of key metabolic pathways have emerged through study of patient tissue samples and preclinical modeling. Among the potentially targetable vulnerabilities are glucose metabolism via glycolysis, oxidative phosphorylation, amino acid and polyamine metabolism, and NAD metabolism. Although few agents have yet to move forward into clinical trials for pediatric cancer patients, the robust and promising preclinical data that have been generated suggest that future clinical trials should rationally test metabolically targeted agents for relevant disease populations.
SUMMARY: Recent advances in our understanding of the metabolic dependencies of pediatric cancers represent a source of potential new therapeutic opportunities for these diseases.

DOI: https://doi.org/10.1097/MOP.0000000000000853
Biomed Chromatogr. 2019 Dec 06. e4769

Metabolic and transcriptional changes in seminal plasma of asthenozoospermia patients.

Lianguo Chen, Chao-Wei Wen, Ming-Jie Deng, Ping Li, Zhi-Da Zhang, Zhuo-Hua Zhou, Xianqin Wang.

  This study was designed to investigate the metabolic and transcriptional alterations in seminal fluid caused by asthenozoospermia (AS). To address these issues, the method of metabonomics based on ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and real-time quantitative PCR (RT-qPCR) were performed to identify some crucial biomarkers and transcription levels of the enzymes in seminal fluid. Seminal fluid samples were collected from 87 AS patients and 73 healthy males with normozoospermia (NZ). The quantitative analysis by UPLC-MS/MS showed that 19 metabolites in seminal plasma were associated with AS, and they were involved in several metabolic pathways, such as energy metabolism, purine metabolism, methionine cycle, and branched chain amino acid (BCAA) metabolism. Among these metabolites, the levels of citric acid, malic acid, succinic acid, and pyruvic acid, which are related to energy metabolism, were collectively reduced in the AS group, while the lactic acid level was enhanced. The results indicated that lesser energy source (adenosine triphosphate, ATP) was produced through the anaerobic glycolysis pathway rather than aerobic catabolism of sugar and tricarboxylic acid (TCA) cycle, resulting in deficiency in the power of sperms. Meanwhile, significant differences in metabolic profiles between the AS group and the control group were revealed on partial least squares discriminant analysis (PLS-DA). In addition, RT-qPCR results revealed that the expression levels of 4 genes coding fructokinase (FRK), citrate synthase (CS), succinate dehydrogenase (SDH), and spermine synthase (SMS), which were related to energy metabolism, were decreased in the AS group. The 23 descriptors of differential expression in AS may be valuable for the diagnosis and sequential study on AS. These results will help to highlight the role of sperm inactivity in AS pathogenesis.

Keywords:  RT-qPCR; UPLC-MS/MS; asthenozoospermia; seminal fluid; tricarboxylic acid

DOI:  https://doi.org/10.1002/bmc.4769